RK-0080552

RK-0080552 (RK-552) is a novel, potent, and selective small-molecule inhibitor of the histone methyltransferase NSD2 (also known as MMSET or WHSC1). Discovered through high-throughput screening of small-molecule libraries by researchers at RIKEN and Jichi Medical University, RK-0080552 specifically targets the catalytic SET domain of NSD2, inhibiting its methyltransferase activity with an IC50 of 0.11 μM. It demonstrates high selectivity over other histone methyltransferases such as G9a and SET7/9. By inhibiting NSD2, RK-0080552 reduces the dimethylation of histone H3 lysine 36 (H3K36me2), leading to the transcriptional downregulation of key oncogenic drivers, particularly IRF4, as well as ATM, CCND2, HIF1A, and STAT3. In preclinical models of t(4;14)-positive multiple myeloma, RK-0080552 exhibits selective cytotoxicity, induces apoptosis, and suppresses tumor growth both in vitro and in vivo, showing additive therapeutic effects when combined with pomalidomide.